Severity classes in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorders: a pilot study ..., 2019, Copetti et al.

This study compares complex/severe and simple/mild cases of people with hypermobile EDS and hypermobility spectrum disorder and finds no association between disease severity and either (Beighton) hypermobility or hEDS criteria.

https://www.ncbi.nlm.nih.gov/pubmed/30783660/

I thought you would appreciate this @Jonathan Edwards. I do think there is a reason that many people with an hEDS phenotype are sick but hypermobility itself is not a complete explanation. I’ve often been puzzled by the narrative around hEDS given that so many people have hypermobile phenotypes without any disability. It strikes me that there are some underlying explanatory factors we are missing.

What I have often observed is that while some people with hEDS just get sick gradually and from a young age, there is often a precipitating event, whether an infection, an accident, or an exposure, e.g., fluroquinolone antibiotics.

 

The simplest and most likely explanation is that hypermobility has nothing to do with their problems.

I have never seen any good population study indicating that people satisfying hEDS or HSD criteria have more symptoms than anybody else. From what I saw from Dr Kate Armon's presentation there are recent European studies that, at least for young people, indicate that there is no difference.

 

If you take the hypermobility out, does what is left resemble a gradual onset variant ME/CFS?

Do we know that these patients don't just have ME/CFS but with some minor structural abnormalities that are of little importance?

I do have a few of these I think. Like empty sella, pectus excavatus, hypermobile shoulders, piezogenic papules, curved spine (not sure what the correct term is). So something went a little wrong but it's not clear that this is part of some other syndrome. I did after all have a normal life until the onset of what I currently view s ME/CFS.

 

I don't think we do.

I have hypermobile shoulders and fifth MCP joints, a curved spine, piezogenic papule and anterior mesocapsular stars and I don't have ME, although I do get backache and stomach-ache and various other things.

 

I think the 'causal link' was manufactured by Peter Rowe, Rodney Grahame and Hans Knoop, among others. Rodney Graham has been travelling the world saying people with hypermobility have widespread pain for decades, without ever showing any evidence.

 

There are so many people with horrible syndromes nobody can really explain and that is why I think that we should collaborate more with other patient groups, maybe even work towards building research initiatives whose job is to discover the cause of these syndromes. Something like hEDS and ME/CFS are really just tentative attempts to classify patients. POTS is a classification based on a single abnormality but the POTS researchers say that it's a devastating syndrome with many more symptoms. Sound familiar?

The problem I think is that medicine has largely left the care and research for these patients to psychosomatic medicine which as discipline is so unscientific that it never admits negative results and therefore is unable to make progress. The underlying idea that unexplained means psychosomatic is wrong and is preventing progress. It will be easier to change the way things are currently being done if we work together with as many other patient groups as possible.

 

What I wonder is if it’s a problem of “selecting on the dependent variable.” You see people who are hypermobile and sick. (Sick in many different but still some predictable ways, namely ME, MCAS, POTS, dysautonomia, fibromyalgia, etc.) You start to describe this and eventually say, “Ah, you are sick because you are hypermobile.” Few people ask, “What about all the people who are hypermobile and not subluxating, not in pain, not sick?” Because they have no complaints, they don’t come into the clinic, and so are largely unobserved. They aren’t even in the study I posted above. Our entire conception of the problem is then based on looking at this truncated sample of people who are both hypermobile and sick. Missing are the hypermobile + well and the not hypermobile + sick in precisely the same ways. If we compared these three groups to non-hypermobile, healthy controls, perhaps we could learn something.

One of the ways some people with hEDS get sick that seems unique to them and some other CTDs is that they can have severe and frequent subluxations. These can be very painful and debilitating. Maybe some people who are hypermobile get sick for some totally independent reason Z but their symptoms and complications differ because of the hypermobility. Their hypermobility didn’t necessarily cause their illness. Rather, it poses some specific challenges, given that they are sick.

I am thinking here of the people who were hypermobile and well up until something happened, where the something might be an accident, fluroquinolone antibiotics, or an infection. There are of course people with hEDS who have been subluxating and getting injured or had gradual onset of dysautonomia and other symptoms since they were kids. They strike me as being in a perhaps a very different situation from the person who was fine until they had an infection. I worry that for the sudden onset case, hypermobility becomes a post-hoc explanation for their symptoms when, as others have said, hypermobility is common in the population.

There is one theory going around that it’s all about mast cell activation and collagen breakdown, which might have different implications for someone with hypermobility v. w/o. I think this is an interesting idea and might explain why hypermobility could be a risk factor for developing ME. Remember that in this sample, everyone is hypermobile. We know hypermobility doesn’t correlate with disability, but there might be other unseen genetic factors that correlate with hypermobility but are also present in people without a hypermobile phenotype, and that predispose people to developing certain chronic illnesses.

In sum: This study suggests it’s not about how hypermobile you are, but that doesn’t mean that hypermobility doesn’t matter. Hypermobility may affect your clinical presentation in important ways without actually causing your illness. It may also correlate with something else that does have some explanatory power but is unlikely to be unique to hypermobility or to be a sufficient condition for developing a chronic illness.

 

Many descriptions of POTS sound exactly like ME. It’s incredibly frustrating.

I couldn’t agree more that our clinicians and researchers should be talking to each other. We’d get a lot done much faster.

 

There are plenty of hEDS patients who developed symptoms after something sudden, whether an infection, accident, environmental exposure, or drug (i.e., fluroquinolone antibiotic). There are also patients who have been sick and gradually worsening since they were 8.

In the US, whether you get diagnosed with ME/CFS, POTS, hEDS or chronic Lyme not infrequently depends on where you live, what healthcare you have access to, and luck. Some proportion of people in all these groups are ME/CFS patients.

 

That is the way I have always assumed the story arose - having been there at the start in 1978.
I have been asking about the other people ever since. Fortunately it looks as if some European groups have been asking the question in population based studies and, as expected, hypermobility does not seem to relate to anything much in the way of symptoms.

But why even suggest that? What reason to we have to think this any more than the causal link?

Mast cell activation does not lead to collagen breakdown. One of the most typical features of the mast cell response is that it is transient and leaves no long term change - as in a bee sting or nettle rash. As far as I can see the 'MCAS' story is the same as the hEDS story - a spurious connection driven by detection bias. There was a recent paper looking I think at EDS, POTS and MCAS and indicating no association is found if you do not start with a skewed sample. A connection between MCAS and EDS doesn't make sense anyway because any relation they might have to connective tissue would be unrelated anyway.

One of the things I hope may come out of the big proposed genetic study in the UK is a clear answer about the relation (or absence of) between these things. I think we already know there is none but assessing a full sample prospectively will be good.

 

It’s also important to note that in hEDS there ARE families with clear inheritance patterns and multiple people affected across generations with no clear shared environmental explanation.

As with so many of these conditions, absent objective markers, definitions are going to be very difficult and yield heterogenous groupings of patients.

 

I think people wonder this because so many of the onset triggers and/or factors that cause a worsening of symptoms in people with ME also cause mast cell degranulation and/or are associated with MMPs. For people with hEDS, they observe an association between MCAS onset or flares and worsening subluxations. Of course this could work in either direction. When I was having constant subluxations in my thoracic spine a few months ago, it would cause my MCAS to flare, possibly due to the irritation of my spine or just as a function of pain. (Pain is an MCAS trigger for me and for many.)

We don’t yet know if there is a causal link but it’s worth keeping open the possibility that there is something correlated with hypermobility but not exclusive to hypermobility that is also correlated with developing ME/CFS/POTS/dysautonomia etc.

MCAS, that is, chronic mast cell activation, is something that we just don’t know a lot about yet. It’s a pretty new concept and has not been well-researched. Certainly, mast cells can release MMP-9s that do break down collagen. It is meant to be part of a normal, short-term immune response. We yet don’t know what implications this could have if it is happening at a chronic, almost continuous basis: if collagen breakdown could be increased or repair/assembly affected.

Certainly since developing MCAS, I have had significant connective tissue changes. This plausibly could be causal but we have no idea yet.

Yes, this is possible. We’d need to find out.

Can you post the link if you have it?

Yes and no. The two don’t need to be causally related to be meaningfully associated. Someone could have a hypermobile phenotype and then develop MCAS. Their MCAS might affect them differently than it would someone without a hypermobile phenotype. They then form a pool of people who are diagnosed with hEDS + MCAS (who are sicker than people with just one of these diagnoses). So we observe that the two seem correlated. There might be no causal relationship as far as etiology is concerned, but it could still be clinically relevant in terms of how the patient is affected and how MCAS might relate to their symptoms.

 

There are families with EDS with clear inheritance patterns. I have been going the rounds in the UK talking to as many colleagues as I can with expertise in this area. It is pretty much unanimously agreed that hEDS is an unhelpful term. The only people who like it are the private clinicians who over diagnose it.

There are very objective markers of EDS. Clearly abnormal joints or skin. When you see someone with actual EDS it is pretty obvious in my experience.

 

Our family has quite a few people with what for decades was simply called hypermobility. I don't understand why we can't just continue with this term, as it's not exactly uncommon – specially in women.

Some of us have subluxations and some don't, just as some of the redheads are able to tan in the sun and some aren't. I got both the subluxations and the inability to tan, but that's the luck of the draw!

 

What about mastocytosis , and various conditions where tryptase is consistently rather than transiently elevated?

Would that not possibly lead to collagen breakdown?

If tryptase is elevated constantly w masto, and only transiently with idiopathic mcas, i wonder what the threshold needed to do damage is

 

Just quoting one thing as a starting point:

I was just gonna jot down some thinking-out-loud-thoughts/questions/speculations I had upon reading through the thread:

1. If hypermobility is sort of a red herring (apart from causing problems by itself when one is in a certain state of illness) and people have e.g. genetic abnormalities which make one more likely to be hypermobile but also contribute to some other vulnerability it might tie loosely and vaguely into the equally vague collagen breakdown thingy.
2. Said collagen breakdown is not really established as far as I know, but didn't we have an increase in circulating hydroxyproline in one or two studies recently? Maybe we are not dealing with collagen breakdown per se either but other possible candidates, e.g. defects in elastin instead of collagen, defective collagen protein construction which somehow leads to increased turnover and thus more hydroxyproline elsewhere etc (just making things up as I go here, I don't know enough to even know if anything is coherent - I guess I am just trying to say that there is probably a lot that could go on in connective tissue that might be a bit harder to pin down). If that leads to problems with blood vessels like less/delayed reaction to normal regulation of widening/tightening due to less elasticity it could lead to number...
3. Mast cells cause flushing (and a lot of other things) when they degranulate if I understood correctly. I assume they are doing this by transiently increasing bloodflow to a region. If there is a problem with blood vessels, could regular functioning mast cells cause issues?

I sometimes have less brainfog after taking an antihistamine and improved sleep even when I don't have any other allergy symptoms, but it doesn't always work the same way. I also get markedly reduced brain fog from beta-alanine which is supposed to mop up free histidine. I cannot tell from experience when the antihistamine will help, I usually respond to the beta-alanine. Benefits are very short-lived and not exactly lifechanging though.

 

Pretty much all proteolytic enzymes within the body (i.e. not in the gut lumen) are balanced out by inhibitors unless very specific signals shift that control. I do not know much about mastocytosis but having spent my career working on diseases that lead to collagen breakdown I have never heard of it being a cause of connective tissue failure.

Apart from anything, ligamentous laxity requires a very specific removal of collagen at very specific places. The simple idea that high enzyme levels will cause tissue laxity bears no relation to reality. All the stuff I have seen about mast cells disorders and collagen damage is just word salad as far as I can see.

 

Oddly when I search this i find some papers saying the opposite, that tryptase can stimulate collagen synthesis/tissue remodelling
https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2222.1998.00467.x

https://www.jci.org/articles/view/119290/version/1/pdf/render